Process for preparing 5-hydroxybenzo [b] thiophene-3-carboxylic acid derivatives

ABSTRACT

Processes for producing compounds of the formula (VI) are disclosed. Benzothiophenecarboxylic acid derivatives of the formula (I), which are useful as starting materials for producing drugs, are disclosed. Particularly, disclosed is a process for preparing 5-dydroxybenzo[b]-thiophene-3-carboxylic acid derivatives of the formula (VI), which are specific PGD 2  antagonists are also disclosed.

This application is a divisional application of Ser. No. 09/647,354,filed Sep. 29, 2000, U.S. Pat. No. 6,320,060 Nov. 20, 2001, which inturn is a 35 U.S.C. 371 of PCT/JP99/01616 filed Mar. 30, 1999.

TECHNICAL FIELD

The present invention relates to 5-hydroxybenzo[b]thiophene-3-carboxylicacid derivatives which are key starting materials for producingcompounds useful in the field of pharmaceuticals.

BACKGROUND ART

5-Hydroxybenzo[b]thiophene-3-carboxylic acid derivatives of the generalformula (I):

wherein R is hydrogen or a hydroxy-protecting group are importantstarting materials in the synthesis of pharmacologically activecompounds. For example, a compound of the formula (I) is essential inthe synthesis of benzothiophenecarboxamide derivatives of the generalformula (VI):

wherein R is as defined above and X is hydrogen or alkyl. Thebenzothiophenecarboxamide derivatives are specific antagonists of PGD₂and known to be useful as a drug in the treatment of various diseasesrelated to mast cell dysfunction caused by excessive production of PGD₂,for example, systemic mastocytosis, disorder of systemic mast cellactivation, tracheal contraction, asthma, allergic rhinitis, allergicconjunctivitis, urticaria, injury due to ischemic reperfusion,inflammation, and atopic dermatis (WO97/00853, PCT/JP97/04527(WO98/25919)). Among compounds of the formula (VI), a compound whereinOR is 5-hydroxy and X is hydrogen (hereinafter, referred to as “CompoundA”) has especially high antagonistic effect on PGD₂, showing anexcellent anti-nasal occlusion activity, and is contemplated to be apromising drug for treating nasal occlusion.

DISCLOSURE OF THE INVENTION

A process for preparing the above-mentioned compound is illustrated bythe following reaction scheme (WO98/25919):

In order to clinically apply Compound A widely, it is essential toestablish a process for preparing a starting material, the compound (I),which process is safe, efficient and industrially applicable.

However, it is difficult to synthesize benzothiophene derivatives having5-hydroxyl group like the compound (I) and there have been no methodsindustrially applicable so far. The existing methods involve variouscomplicated processes and are inefficient and of low yield. For example,there have been methods wherein 5-acetoxybenzo[b]thiophene is brominatedto yield 3-bromo-5-acetoxybenzo[b]thiophene, which in turn isre-protected at the 5-acetoxy group with a benzyl group to yield3-bromo-5-benzyloxybenzo[b]thiophene, which is followed by metallizationwith magnesium, introduction of carbon dioxide and removal of the benzylgroup (J. Chem. Soc. (C). 1967, 1899-1905); or 5-bromobenzo[b]-thiopheneis subjected to Friedel-Crafts reaction to yield3-acetyl-5-bromobenzo[b]thiophene, which is followed by oxidation withsodium hypochlorite to yield 5-bromobenzo[b]thiophene-3-carboxylic acid(Nippon-Kagaku Zasshi vol. 86, No. 10, 1067-1072(1965), J. Chem. Soc.(C). 1967, 2084-2089). 5-Hydroxybenzo[b]thiophene-3-carboxylic acid or5-acetoxybenzo[b]thiophene-3-carboxylic acid are then synthesizedstarting from the reaction products above. However, the startingmaterial such as 5-hydroxybenzo[b]thiophene or 5-bromobenzo[b]thiopheneis not commercially available and had to be synthesized from anappropriate reagent (e.g., J. Am. Chem. Soc., 57, 1611(1935), J.Heterocyclic Chem., 25, 1271(1988)) in all cases, which have made thesynthetic process longer and complex.

The present invention solves the problems of the existing methods andprovides a method for the preparation of the compounds of the formula(I), which method is industrially applicable, efficient and safe.

Thus, the present invention provides a process for preparing a compoundof the formula (I):

wherein R is hydrogen or a hydroxy-protecting group, or a reactivederivative thereof comprising subjecting 4-mercaptophenol to reactionsfor introduction of a propargyl group and protection of hydroxyl groupto yield a compound of the formula (II):

wherein R¹ is a hydroxy-protecting group; oxidizing the compound (II) toyield a compound of the formula (III):

wherein R¹ is a hydroxy-protecting group; subjecting the compound (III)to thermal rearrangement reaction to yield a compound of the formula(IV):

wherein R¹ is as defined above; and subjecting the compound (IV) tostepwise oxidation of hydroxymethyl group and optionally deprotection.

The present invention also provides a process for preparing a compoundof the formula (I):

wherein R is hydrogen or a hydroxy-protecting group or a reactivederivative thereof comprising subjecting 5-hydroxybenzo[b]thiophene to aprotecting reaction to yield a compound of the formula (VII):

wherein R² is a hydroxy-protecting group; reacting the compound (VII)with acetyl halide under the conditions for Friedel-Crafts reaction toyield a compound of the formula (VIII):

wherein R² is a hydroxy-protecting group; and subjecting the compound(VIII) to oxidation of the acetyl group and optionally deprotection.

The present invention further provides a method for the preparation ofthe above-mentioned 5-hydroxybenzo[b]thiophene-3-carboxylic acidderivative of the general formula (VI) by using a compound of theformula (I). Thus, the present invention provides a process forpreparing a compound of the formula (VI):

wherein R is as defined above and X is hydrogen or alkyl, and doublebond represents either E- or Z-configuration, or a pharmaceuticallyacceptable salt thereof or a hydrate thereof, which comprises subjectinga compound of the formula (I) or a reactive derivative thereof to thefollowing reactions:

(1) reaction with a compound of the formula (V)

wherein X is hydrogen or alkyl; or

(2) reaction with a compound of the formula (V′):

or a salt thereof followed by oxidation and reaction with an ylide underthe conditions for Wittig reaction; and

(3) optionally deprotection.

THE BEST EMBODIMENT FOR PRACTICING THE INVENTION

The terms used herein are defined below.

The term “hydroxy-protecting group” means alkyl, alkoxyalkyl, acyl,aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl,alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl ortetrahydropyranyl.

The term “alkyl” means C₁-C₂₀ linear or branched alkyl, particularly,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like, andC₁-C₆ alkyl is preferred.

The term “alkoxy” means C₁-C₆ linear or branched alkoxy, particularly,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy,t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy,t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxyand the like, and C₁-C₃ alkoxy is preferred.

The term “alkoxyalkyl” means alkyl group substituted by alkoxy group,including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl,methoxypropyl and the like.

The term “acyl” means C₁-C₁₁ acyl derived from aliphatic carboxylic acidor aromatic carboxylic acid. Examples of aliphatic carboxylicacid-derived acyl include acetyl, chloroacetyl, trichloroacetyl,propionyl, butyryl, valeryl and the like, and examples of aromaticcarboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl,p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl and the like.

The term “aryl” means phenyl, naphthyl or polycyclic aromatichydrocarbon group and the like. In addition, aryl may be substituted bythe following substituents.

Examples of substituent include alkyl such as methyl, ethyl, n-propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl or tert-pentyl, lower alkoxy such as methoxy or ethoxy,halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy, carboxy,cyano, sulfonyl, amino, lower alkylamino such as methylamino,dimethylamino, ethylmethylamino or diethylamino, and the like. The arylgroup may have one or more substituents at any possible positions.Specific examples of aryl include 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl,4-(N,N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and thelike.

The aryl group in the “aralkyl”, “arylsulfonyl”, “aryloxycarbonyl” or“aralkyloxycarbonyl” described below may have similar substituents asdefined above.

The term “aralkyl” means an alkyl group substituted by aryl group, andincludes benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,naphthylmethyl, phenethyl, and the like.

The term “alkylsulfonyl” means a sulfonyl group substituted by alkylgroup, and includes methanesulfonyl, ethanesulfonyl and the like.

The term “arylsulfonyl” means a sulfonyl group substituted by arylgroup, and includes benzenesulfonyl, p-toluenesulfonyl, and the like.

The term “alkyl-substituted silyl” means mono-, di- ortri-alkyl-substituted silyl, for example, methylsilyl, dimethylsilyl,trimethylsilyl, t-butyldimethylsilyl, and the like.

The term “alkoxycarbonyl” means methoxycarbonyl, isopropoxycarbonyl,t-butoxycarbonyl, and the like.

The term “aryloxycarbonyl” means phenoxycarbonyl, and the like.

The term “aralkyloxycarbonyl” means benzyloxycarbonyl, and the like.

Although all the above-mentioned hydroxy-protecting groups are preferredas the hydroxy-protecting group shown by R¹, R² or R in respectiveformula above, aryl sulfonyl is more preferred and benzenesulfonyl isparticularly preferred among them.

Examples of salts of the compound of the general formula (VI) includealkali metal salts such as lithium salt, sodium salt or potassium saltand the like, alkali earth metal salts such as calcium salt and thelike, ammonium salt, salts with organic base such as tromethamine,trimethylamine, triethylamine, 2-aminobutane, tert-butylamine,diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine,tri-n-butylamine, cyclohexylamine, dicyclohexylamine,N-isopropylcyclohexylamine, furfurylamine, benzylamine,methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine,2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine,diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene,2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine,or amino acid salts such as lysine salt or arginine salt.

The salts of the amino alcohol of the formula (V′) include salts withorganic acid such as benzoic acid, etc., and mineral acid such ashydrochloric acid, sulfuric acid, etc.

The final compound of the present invention is represented by theformula (VI) as described above, in which the double bond of thealkenylene side chain (5-heptenylene chain) may be in the E- orZ-configuration.

The method of the present invention is described below in more detail.When a substituent(s) possibly interfering the reaction is present, itcan be appropriately protected and then deprotected at a desired stage.Such protection or deprotection can be accomplished by a procedure knownin the art.

Wherein R and R¹ are as defined above.

[Step 1]

This step is related to the introduction of a propargyl group at themercapto group of 4-mercaptophenol (1) and protection of hydroxyl group.

The introduction of a propargyl group is accomplished by using propargylhalide such as propargyl bromide, propargyl chloride and the like in thepresence of a basic agents. The reaction can be accomplished withinseveral tens minutes to several hours at room temperature by employing,as a basic agent, inorganic base such as potassium carbonate, sodiumcarbonate or the like, or an organic base such as triethylamine,pyridine, 4-dimethylaminopyridine or the like in a solvent such asacetone, ethyl acetate, tetrahydrofuran, acetonitrile, or the like.

When a strong base such as potassium hydroxide or sodium hydroxide isused, it can be also accomplished in a two-layer solvent system such astoluene-water or xylene-water.

The protection of hydroxyl group may be conducted using an ordinaryhydroxy-protecting group in a conventional manner. Preferred protectinggroups to be used in the present method are those which do not undergochanges during the oxidative reactions in the 2nd and 4th steps of thepresent Process and the 2nd step of Process IV below for the preparationof compound of the formula (VI) and also during the Wittig reaction ofthe 3rd step of said Process, and can be easily deprotected in the 4thstep to give leaving groups which are easily separable from, forexample, Compound A for purification thereof, which corresponds to acompound of the formula (VI) wherein OR is 5-hydroxy, X is hydrogen anddouble bond is in Z-configuration. Examples of such a hydroxy-protectinggroup include alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl,arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl,aralkyloxycarbonyl or tetrahydropyranyl.

Considering the requirements that a protecting group should surviveduring the Wittig reaction conducted under strong basic conditions, beeasily deprotected, for example, in the 4th step for the preparation ofCompound A, and be separable from Compound A, arylsulfonyl is morepreferred and benzenesulfonyl is particularly preferred. Benzenesulfonylgroup is relatively stable to base in anhydrous solvents and, upondeprotection, gives benzenesulfonic acid which is water-soluble and iseasily separated from the final product of the formula (VI). Theprotection and deprotection can be carried out by a method known in theart. For example, in the case of benzenesulfonyl group, the introductionof benzenesulfonyl group is carried out in a manner similar to that forthe introduction of propargyl group by using benzenesulfonyl chloride.

[Step 2]

This step is related to oxidation of the compound (II).

There have been known oxidizing methods which use, for instance, aqueoushydrogen peroxide—acetic acid (J. Am, Chem. Soc., 87, 1109-1114 (1965)),aqueous hydrogen peroxide—titanium(III) chloride (Synthesis 1981,204-206), m-chloroperbenzoic acid (Org. Synth., 64, 157-163 (1985)), orsodium metaperiodate (J. Org. Chem., 27, 282-284 (1962)).

In the present step, it is preferred to use a slightly excess amount of30% aqueous hydrogen peroxide in an alcoholic solvent such as ethanol,methanol, isopropanol or tert-butanol solution containing formic acid.The reaction is accomplished within several tens minutes to severalhours under cooling or at room temperature.

[Step 3]

This step is related to the conversion of the compound (III) into thehydroxymethyl compound (IV) by thermal rearrangement reaction. Thethermal rearrangement reaction in this step is carried out according tothe method described in J. C, S. Chem. Comm., 1974, 848-849. Examples ofpreferred solvents for this reaction include dioxane,1,2-dimethoxyethane, propyl acetate and 3-pentanone. The reaction isaccomplished by refluxing in a solvent for several hours followed byadding to the resultant intermediate an acid (p-toluenesulfonic acid,methanesulfonic acid, sulfuric acid, etc.) [Step 4]

This step is related to the oxidation of the compound (IV) to providecarboxylic acid (I). The oxidation can be carried out either directly orin a stepwise manner. Examples of oxidizing agent for converting anaromatic primary alcohol to the corresponding carboxylic acid directlyinclude chromic acids (Synthesis. 1986, 285-288), potassium permanganate(J. Org. Chem., 18, 806-809 (1953)) and ruthenium oxides (J. C. S. Chem.Comm., 1979, 58-59)). However, these methods have disadvantages in notonly the yield but also the following matters. For instance, thereaction time is long, the detoxification treatment of oxidizing agentis needed following the reaction, the reagents are unstable and/or theyinvolve complicated operations.

On the contrary, in some cases, a stepwise oxidation wherein a primaryalcohol is oxidized to an aldehyde and then to a carboxylic acid may beof advantage with regard to yield. In general, the oxidation of alcoholto aldehyde has been carried out by using an oxidizing agent of chromicacid series, for example, Jones reagents (J. Org. Chem., 40, 1664-1665(1975)), Collins reagents (J. C. S. Chem. Comm., 1972 1126)), pyridiniumchlorochromate (Tetrahedron Lett., 2647-2650 (1975)). It has been alsoknown a method which uses manganese dioxide (Helv. Chim. Acta., 39,858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J. Org. Chem.,43, 2480-2482 (1978)). However, these existing methods havedisadvantages. For example, chromic acids are toxic to human body andmust be detoxified after use. Further, the Swern oxidation usingdimethyl sulfoxide-oxalyl chloride is not suited for a large scaleproduction because it is accompanied by the generation of carbonmonoxide harmful to workers and sulfurous odor and also it must becarried out at low temperature, for example, between −50° C. and −78° C.

Alcohol (IV) can be converted into aldehyde (IV′) almost quantitativelyby a method wherein an alcohol (IV) is oxidized with an oxidizingreagent such as halo oxoacid in the presence of2,2,6,6-tetramethylpiperidine-1-oxyl or the like (referred to as“TEMPOs”) according to the description in a literature (e.g., J. Org.Chem., 52, 2559-2562 (1987)), whereby the problems of the existingmethods are solved. Examples of TEMPOs usable include2,2,6,6-tetramethylpiperidine-1-oxyl,4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl,4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl,4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl. Examples of usable halooxoacids include sodium hypochlorite, sodium hypobromite, sodium bromiteand higher bleaching powder. A solution of an oxidizing agent may beadjusted to, for example, pH 8.5 to 9.5 with a mineral acid such assodium hydrogen carbonate, hydrogen chloride or sulfuric acid.Alternatively, a solution of an oxidizing agent may be added in thepresence of sodium hydrogen carbonate. The reaction can be accomplishedwithin several minutes to several tens minutes at temperature fromice-cooling to room temperature in a solvent such as ethyl acetate,acetonitrile or dichloromethane.

When the reaction solution containing the resultant aldehyde (IV′) isacidified and sodium chlorite and aqueous hydrogen peroxide are addedthereto, the aldehyde is converted into carboxylic acid underice-cooling within several tens minutes to several hours.

If desired, the product may be further subjected to the deprotection of5-hydroxy-protecting group and/or conversion into reactive derivativesat 3-carboxyl group. Such “reactive derivative” includes thecorresponding acid halides (e.g., chloride, bromide, iodide), acidanhydrides (e.g., mixed acid anhydride with formic acid or acetic acid),activated esters (e.g., succinimide ester), and the like, and includesacylating agents generally used for the acylation of amino group. Forexample, to obtain acid halides, a carboxylic acid is reacted withthionyl halide (e.g., thionyl chloride), phosphorous halide (e.g.,phosphorous trichloride, phosphorous pentachloride), oxalyl halide(e.g., oxalyl chloride), or the like, according to a known method (e.g.,Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis852-854(1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)).

wherein R and R² are as defined above.

[Step 1]

This step is related to the protection of 5-hydroxy group of compound(7).

The compound (7) as the starting material of the present step is knownin a literature (J. Am. Chem. Soc., 57, 1611-1616 (1935), Ann. Chem.,527, 83-114 (1938), J. Am. Chem. Soc., 78, 5351-5357 (1956), J. Org.Chem., 41, 1118-1124 (1976)). The hydroxyl group of this compound isprotected appropriately in a manner similar to that described in the 1ststep of Process I above. For example, when benzenesulfonyl group isused, the compound is added to benzenesulfonyl chloride in the presenceof an inorganic base such as sodium carbonate or potassium carbonate, oran organic base such as triethylamine or tripropylamine. Example ofpreferred solvent includes acetone, ethyl acetate and tetrahydrofuran.The reaction is accomplished within several minutes to several hours attemperature from room temperature to the boiling point of the solvent.The compound (VII) can be also synthesized by a broadly used method,commonly known as “Schotten-Baumann reaction”.

[Step 2]

This step is related to the introduction of acetyl group to the3-position of the compound (VII) by Friedel-Crafts reaction. Theintroduction of acetyl group is, for example, carried out using acetylchloride or acetyl bromide in the presence of a catalyst, for example, aLewis acid such as aluminium chloride, ferric chloride, zinc chloride,tin chloride and boron trifluoride. Example of usable solvent includescarbon disulfide, nitrobenzene or a halogenated hydrocarbons such asmethylene chloride or ethylene chloride. The reaction is in generalaccomplished within several hours at temperature of ice-cooling to roomtemperature. The 2-acetyl compound slightly produced as a by-product iseasily separable by recrystallization.

[Step 3]

This step is related to the conversion of the compound (VIII) into acarboxylic acid (I) or a reactive derivative thereof through theoxidation of the acetyl group in the presence of a salt of hypohalousacid. Examples of preferred hypohalogenite include alkali metal oralkaline earth metal salts of hypohalous acids, and potassium, sodium orcalcium salt of hypochlorous or hypobromous acid is especiallypreferred.

In an aqueous solution of such a salt, the oxidation progresses atrelatively low temperature. However, dioxane or 1,2-dimethoxyethane maybe used as a solvent so as to increase the solubility of the compound tobe oxidized. The reaction is accomplished within several hours toseveral tens hours at room temperature or with heating.

wherein R and X are as defined above and the double bond represents E-or Z-configuration.

This process is related to the synthesis of a compound of the formula(VI) by reacting a compound of the formula (I) or a reactive derivativethereof obtained in Process I or II above with a compound of the formula(V).

The compound (V) used in the present process is obtainable according tothe method described in Japanese Patent Publication (KOKOKU) No. 6-23170(23170/1994).

The reaction can be carried out under ordinary conditions for acylationof amino group. For example, when a carboxylic acid halide is used, thereaction is carried out according to a method commonly known as“Schotten-Baumann reaction”. In general, carboxylic acid halide is addeddropwise to an aqueous alkaline solution of amine with stirring andunder cooling while removing the generating acid with alkali.Alternatively, when a carboxylic acid is used as a free acid not areactive derivative, the reaction can be conducted conventionally in thepresence of a coupling agent generally used in the coupling reactionbetween an amine and a carboxylic acid such as dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide orN,N′-carbonyldiimidazole.

wherein R and X are as defined above and the double bond represents E-or Z-configuration.

[Step 1]

This step is related to the preparation of a compound of the formula(IX) by reacting a compound of the formula (I) or a reactive derivativethereof with a compound of the formula (V′) or its salt in a mannersimilar to that described in Process III above. The preparation of someof the compounds of the formula (VI) is described in Chem. Pharm. Bull.Vol.37, No. 6 1524-1533 (1989).

[Step 2]

This step is related to the preparation of an aldehyde of the formula(X) by oxidizing a compound of the formula (IX). The reaction can becarried out for several hours under cooling or at room temperature usingan oxidizing agent selected from chromic acid series such as Jonesreagents, Collins reagents, pyridinium chlorochromate, pyridiniumdichromate or dimethyl sulfoxide-oxalyl chloride in a solvent such aschlorinated hydrocarbons (chloroform, dichloromethane, etc.), ethers(ethyl ether, tetrahydrofuran, etc.), acetone or benzene.

[Step 3]

This step is related to the formation of a double bond by reacting acompound of the formula (X) with an ylide (Ph₃P═CH(CH₂)₃COOH). Thereaction for providing a double bond can be carried out in aconventional manner for Wittig reaction. The ylides used in the reactioncan be synthesized, in the presence of a base, by treating a phosphoniumsalt which has been synthesized from triphenylphosphine and an alkylhalide having a desired alkyl group to be condensed, for example,5-bromopentanoic acid. Examples of a base include dimsyl sodium, dimsylpotassium, sodium hydride, n-butyl lithium, potassium t-butoxide andlithium diisopropylamide. The reaction is accomplished within severalhours at room temperature in a solvent such as ether, tetrahydrofuran,n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide.

[Step 4]

In this step, a compound (VI) wherein R is hydroxy-protecting group isoptionally deprotected to give compound (VI-1). The reaction can becarried out in a conventional manner using a catalyst such ashydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxideor barium hydroxide, or the like. The reaction is accomplished withinseveral tens minutes to several hours with heating in a solvent such asmethanol-water, ethanol-water, acetone-water, acetonitrile-water, or thelike, preferably dimethyl sulfoxide-water.

The following Examples are provided to further illustrate the presentinvention in more detail and should not be interpreted in any way as tolimit the scope thereof. The abbreviations used in the Examples have thefollowing meanings:

Ph: phenyl

Ac: acetyl

TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl

EXAMPLE 1 (1) Step 1 4-(2-Propyn-1-ylthio)phenyl benzenesulfonate (2)

4-Mercaptophenol (1) (37.85 g, 300 mmol) and propargyl bromide (42.82 g,360 mmol) were dissolved in ethyl acetate (757 ml). To the solution wasadded dropwise triethylamine (42.5 g, 420 mmol) over 25 minutes withstirring and under ice-cooling. After stirring for another 1.5 hours atthe same temperature, triethylamine (42.5 g, 420 mmol) was added in oneportion, and benzenesulfonyl chloride (63.58 g, 360 mmol) was addeddropwise over 20 minutes. After keeping 1 hour at the same temperature,the cooling bath was removed and the mixture was stirred for 30 minutesat room temperature and partitioned into two layers by adding ice-water(500 ml) and 2N hydrochloric acid (110 ml). The aqueous layer wasextracted with ethyl acetate (200 ml). The combined organic layer waswashed with water, dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure to provide 100.04 g ofthe title compound (2) as oil. Crude yield: 109%.

IR (CHCl₃); 3306, 3071, 3031, 3019, 3009, 1585, 1486, 1449, 1378 cm⁻¹

¹H NMR δ(CDCl₃), 300 MHz; 2.23 (1H, t, J=2.7 Hz), 3.56 (2H, d, J=2.7Hz), 6.94 and 7.34 (each 2H, each d, J=8.7 Hz), 7.51-7.56 (2H, m), 7.68(1H, m), 7.82-7.85 (2H, m)

(2) Step 2 4-(2-Propyn-1-ylthio)phenyl benzenesulfonate (3)

The compound (2) (60.8 g, 183 mmol) prepared in step (1) above wasdissolved in formic acid (30.4 ml) and methanol (122 ml), and 31%aqueous hydrogen peroxide (26.29 g, 240 mmol) was then added. After 3.5hours, ice-water (240 ml) was added and the mixture was extracted withethyl acetate (2×300 ml). The combined organic layer was washed with 5%aqueous sodium carbonate and water, dried over anhydrous magnesiumsulfate and the solvent was then distilled off under reduced pressure toprovide 65.47 g of the title compound (3) as oil. Crude yield: 117%.

IR (CHCl₃); 3305, 3066, 3032, 3012, 1586, 1486, 1449, 1382 cm⁻¹

¹H NMR δ(CDCl₃), 300 MHz; 2.34 (1H, t, J=3.9 Hz), 3.58 and 3.68 (each1H, each dd, J=3.9 and 23.7 Hz), 7.18 and 7.67 (each 2H, each d, J=9.9Hz), 7.51-7.59 (2H, m), 7.66 (1H, m), 7.82-7.87 (2H, m)

(3) Step 3 5-Benzenesulfonyloxy-3-hydroxymethylbenzo[b]thiophene (4)

The compound (3) (65.47 g, 183 mmol) obtained in above (2) was dissolvedin 1,2-dimethoxyethane (1.6 L) and the solution was refluxed for 4hours. To the solution were added water (64 ml) and p-toluenesulfonicacid monohydrate (19.2 g, 100 mmol) and refluxing was continued for 2hours. The reaction mixture was concentrated under reduced pressure.After water (200 ml) was added to the resulting oil, the mixture wasextracted with ethyl acetate (300 ml). The organic layer was washed withaqueous sodium hydrogen carbonate and water, dried over anhydrousmagnesium sulfate and then the solvent was distilled off under reducedpressure to provide 60.18 g of the title compound (4) as oil. Crudeyield: 103%.

IR (CHCl₃); 3609, 3067, 3033, 3013, 2935, 2878, 1589, 1566, 1449, 1435,1376 cm⁻¹

¹H NMR δ(CDCl₃), 300 MHz; 4.78 (2H, d, J=0.9 Hz), 6.98 (1H, dd, J=2.4and 8.7 Hz), 7.26 (1H, s), 7.43-7.45 (2H, m), 7.50-7.55 (2H, m), 7.66(1H, m), 7.73 (1H, d, J=8.7 Hz), 7.83-7.86 (2H, m)

(4) Step 4 5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6)

The compound (4) (51.26 g, 155 mmol) prepared in above (3) was dissolvedin acetonitrile (1.54 L), and TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 250 mg, 0.01 eq.) was added thereto.To the mixture was added dropwise 0.81 N aqueous sodium hypochlorite,which had been prepared by diluting 1.63 N aqueous sodium hypochlorite(150ml) with water (75 ml), adjusting pH 8.6 with 1 N sulfuric acid, andadjusting the total volume to 300 ml, over 15 minutes, while maintainingthe inner temperature between −1° C. and 8° C. After stirring for 25minutes at this temperature, 1 N aqueous sodium sulfite (32 ml) wasadded. Subsequently, 79% sodium chlorite (27.48 g, 240 mmol) and 31%aqueous hydrogen peroxide (23.26 g, 212 mmol) were added underice-cooling. The cooling bath was removed and the mixture was stirredfor 2 hours. The reaction was diluted with water (1.5 L), adjusted to pH3 with 1 N hydrochloric acid and the deposited crystals were filtered,and washed twice with water (200 ml), acetonitrile (50 ml) to provide32.4 g of crude crystals. The crude crystals (32.4 g) were suspended inacetonitrile (224 ml), refluxed for 15 minutes and cooled on ice. Thecrystals were filtered and washed with acetonitrile (65 ml) to provide26.79 g of the title compound (6). Yield: 51.7%, mp 202-203° C.

IR (Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558, 1500,1460, 1451 cm⁻¹

NMR δ(CDCl₃), 300 MHz; 7.16 (1H, dd, J=2.7 and 9.0 Hz), 7.55-7.61 (2H,m), 7.73 (1H, m), 7.81 (1H, d, J=9.0 Hz), 7.90-7.94 (2H, m), 8.16 (1H,d, J=2.7 Hz), 8.60 (1H, s)

Elemental Analyses for C₁₅H₁₀O₅S_(2 Calculated (%): C,) 53.88; H, 3.01;S, 19.18. Found (%): C, 53.73;H, 3.24; S, 19.09.

EXAMPLE 2 (1) Step 1 5-Benzenesulfonyloxybenzo[b]thiophene (8)

The compound (7) [J. Am. Chem. Soc., 57, 1611-1616 (1935); Ann. Chem.,52, 83-114 (1938), J. Am. Chem. Soc., 78, 5351-5357 (1956); J. Org.Chem., 41, 1118-1124 (1976)] (1.36 g, 9.05 mmol) and triethylamine (1.89ml, 13.6 mmol) were dissolved in tetrahydrofuran (10 ml). To thesolution was added dropwise a solution of benzenesulfonyl chloride (1.92g, 10.9 mmol) in tetrahydrofuran (3 ml). After being stirred for 2hours, the reaction mixture was diluted with water and extracted withtoluene. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and then the solvent was distilled off under reducedpressure. The residue was chromatographed over silica gel (5:1hexane:ethyl acetate) and then recrystallized from hexane containingsmall amount of ethyl acetate to provide 2.28 g of the title compound(8). Yield: 86.8%, mp 80-81° C.

IR (Nujol): 1599, 1579, 1564, 1497, 1448, 1440, 1415, 1352 cm⁻¹

¹H NMR δ(CDCl₃); 300 MHz; 6.92 (1H, dd, J=2.4 and 8.7 Hz), 7.26 (1H, dd,J=0.9 and 5.4 Hz), 7.47 (1H, d, J=2.4 Hz), 7.51 (1H, d, J=5.4 Hz),7.52-7.55 (2H, m), 7.67 (1H, m), 7.74 (1H, d, J=8.7 Hz), 7.83-7.87 (2H,m)

Elemental Analyses for C₁₄H₁₀O₃S_(2 Calculated (%): C,) 57.91; H, 3.47;S, 22.09. Found (%): C, 57.72; H, 3.45; S, 21.98.

(2) Step 2 3-Acetyl-5-benzenesulfonyloxy-benzo[b]thiophene (9)

Powdered aluminum chloride (1.34 g, 10 mmol) was suspended indichloromethane (10 ml). To the suspension was added dropwise acetylchloride (1.02 ml, 14.3 mmol) over 5 minutes with stirring and underice-cooling. Subsequently, a solution of the compound (8) (2.075 g, 7.2mmol) prepared above in dichloromethane (6 ml) was added dropwise over15 minutes. After being stirred for 2 hours at the same temperature andthen for 2.5 hours at room temperature, the solution was poured intoice-water and extracted with dichloromethane. The organic layer waswashed with water, dried over anhydrous magnesium sulfate and then thesolvent was distilled off under reduced pressure. The resulting residuewas recrystallized from ethyl acetate (3 ml) and hexane (3 ml) toprovide 2.01 g of the title compound (9). Yield: 84.4% mp 129-130° C.

IR (Nujol): 3094, 1672, 1619, 1596, 1556, 1494, 1450, 1437, 1428, 1369cm⁻¹

¹H NMR δ(CDCl₃); 300 MHz; 2.58(3H, s), 7.22 (1H, ddd, J=0.6, 2.4 and 9.0Hz), 7.52-7.58 (2H, m), 7.69 (1H, m), 7.79 (1H, d, J=9.0 Hz), 7.87-7.91(2H, m), 8.27 (1H, dd, J=0.6 and 2.4 Hz), 8.31 (1H, s)

Elemental Analyses for C₁₆H₁₂O₄S_(2 Calculated (%): C,) 57.82; H, 3.64;S, 19.29. Found (I): C, 57.62; H, 3.71; S, 19.23.

(3) Step 3 5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6)

The compound (9) (6.65 g, 20 mmol) prepared in above (2) was dissolvedin dioxane (50 ml), and 10% sodium hypochlorite (46.2 ml) was added over20 minutes with stirring while maintaining the temperature at 10-12° C.After 7 hours, the reaction mixture was diluted with ice-water (80 ml)and acidified with conc. hydrochloric acid (5.2 ml). The depositedcrystals were filtered, washed with water, dried to provide 5.84 g ofcrude crystals. The 5.84 g of the crude crystals were recrystallizedfrom methanol (66 ml) and water (16 ml) to provide 5.51 g of the titlecompound (6). Yield: 82.4%. mp 203-204° C.

This compound is identical to the compound (6) prepared in Example 1.

Reference Example 1

5-Benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (10)

5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (5.582 g,16.7 mmol) prepared in Examples above was refluxed for 1.5 hours withdimethylformamide (1 drop), thionyl chloride (3.57 ml, 50 mmol) andtoluene (22 ml), and the solvent was removed under reduced pressure toprovide 5.89 g of the title compound (10).

Reference Example 2 (1) Step 1 5-Hydroxybenzo[b]thiophene-3-carboxylicacid (11)

5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (100 mg, 0.3mmol) prepared in Examples above was dissolved in 1 N sodium hydroxide(1.2 ml) and heated at 40° C. for 8 hours with stirring. To the reactionsolution was added 1 N hydrochloric acid (1.2 ml), and the depositedcrystals were filtered, washed with water and dried to provide 58 mg ofthe title compound (11). Yield: 96.6% mp 262-263° C.

This compound (11) is identical to5-hydroxybenzo[b]thiophene-3-carboxylic acid described in M.Martin-Smith et al. J. Chem. Soc (C), 1899-1905 (1967).

(2) Step 2 5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12)

5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11) (1,140 mg) prepared inabove (1) was dissolved in acetic anhydride (2 ml), pyridine (4 ml).After 3 hours, water was added and the mixture was continuously stirredunder ice-cooling for 1.5 hours. The deposited crystals were filtered,washed with water and dried to provide 1,349 mg of the title compound(12). Yield: 97.3% mp 239-240° C.

¹H NMR δ(CDCl₃), 300 MHz; 2.37(H, s), 7.20 (1H, dd, J=2.4 and 8.7 Hz),7.87 (1H, d, J=8.7 Hz), 8.34 (1H, d, J=2.4 Hz), 8.57 (1H, s)

(3) Step 3 5-Acetoxybenzo[b]thiophene-3-carbonyl chloride (13)

5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12) (1,349 mg) preparedabove was refluxed for 1.5 hours with dimethylformamide (1 drop),thionyl chloride (1.22 ml) and toluene (25 ml). The solvent was removedunder reduced pressure to provide 1,454 mg of the title compound (13).

EXAMPLE 3(5Z)-7-[(1R,2R,3S,5S)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (17)

(1) Step 1 Preparation of[3-[(1R,2R,3R,5S)-3-(2-Hydroxyethyl)-10-norpinan-2-yl]carbamoylbenzo[b]thiophen-5-yl]benzenesulfonate(14)

Benzoic acid salt of(+)-2-[(1R,2R,3R,5S)-2-Amino-10-norpinan-3-yl]ethanol (described inChem. Pharm. Bull. Vol.37, No. 6 1524-1533(1989) (V′-1)) (5.1 g, 16.7mmol) was suspended in water (10 ml). To the suspension was added 1 Nhydrochloric acid (17 ml) and deposited benzoic acid was removed byextracting with ethyl acetate. The organic layer was washed with water(10 ml). To the combined aqueous layer was added 4 N sodium hydroxide(9.2 ml, 36.8 mmol) under ice-cooling. A solution of5-benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (10) (5.89g,16.7 mmol) in tetrahydrofuran (36 ml) was then added dropwise over 15minutes with stirring. After stirring for 1 hour at the sametemperature, 1 N hydrochloric acid (4 ml) was added and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and then the solvent wasdistilled off under reduced pressure to provide 8.00 g (95.6%) of thetitle compound (14) as colorless amorphous.

¹H NMR δ(CDCl₃), 300 MHz; 0.96 (1H, d, J=9.9 Hz),1.12 and 1.26 (each 3H,each s), 1.50-2.42(9H, m), 3.69-3.82 (2H, m), 4.30 (1H, m), 6.21 (1H, d,J=8.1 Hz), 7.06 (1H, dd, J=2.4 and 8.7 Hz), 7.51-7.56 (2H, m), 7.67 (1H,m), 7.73 (1H, d, J=8.7 Hz), 7.85 -7.88 (2H, m), 7.88 (1H, s), 8.06 (1H,d, J=2.4 Hz).

[α]_(D) ²⁵+35.7° (c=1.00%, CH₃OH)

(2) Step 2 Preparation of[3-[(1R,2R,3R,5)-3-Formylmethyl-10-norpinan-2-yl]carbamoylbenzo[b]thiophen-5-yl]benzenesulfonate(15)

To dimethyl sulfoxide (3.16 ml, 44.5 mmol) dissolved in dimethoxyethane(50 ml) was added oxalyl chloride (1.91 ml, 21.9 mmol) under cooling at−60° C.-−65° C. A solution of compound (14) (7.352 g, 14.7 mmol) in1,2-dimethoxyethane (58 ml) was added dropwise at the same temperature.After stirring the mixture at −55° C.-−60° C. for 30 minutes,triethylamine (6.1 ml) was added and, 30 minutes later, the cooling bathwas removed to allow the mixture to warm up to room temperature. Thereaction mixture was diluted with water (100 ml) and extracted withtoluene. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and then the solvent was distilled off under reducedpressure. The resulting residue was purified by chromatography on silicagel (hexane:ethyl acetate=5:5-4:6) to provide 7.32 g (100%) of the titlecompound (15) as colorless amorphous.

IR (CHCl₃); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729, 1720,1655, 1599, 1558, 1513, 1377 cm⁻¹

¹H NMR δ(CDCl₃), 300 MHz; 0.97 (1H, d, J=10.2 Hz), 1.17 and 1.28(each3H, each s), 1.46 (1H, m), 2.03 (1H, m), 2.22 (1H, m), 2.36-2.60(3H, m),2.69 (1H, ddd, J=1.2, 8.7 and 17.4 Hz), 3.14 (1H, dd, J=4.5 and 17.4Hz), 4.28 (1H, m), 6.18 (1H, d, J=8.1 Hz), 7.09 (1H, dd, J=2.4 and 8.7Hz), 7.50-7.55 (2H, m), 7.67 (1H, m), 7.75 (1H, d, J=8.7 Hz), 7.85-7.89(2H, m), 7.89 (1 H,s), 8.03 (1H, d, J=2.4 Hz), 9.80 (1H, d, J=1.2 Hz)

[α]_(D) ²³+31.8° (c=1.00%, CH₃OH)

(3) Step 3 Preparation of(5Z)-7-[(1R,2R,3S,5S)-2-(5-Benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (16)

4-Carboxybutyltriphenylphosphonium bromide (12.17 g, 27.5 mmol) andpotassium t-butoxide (7.19 g, 64.1 mmol) were suspended intetrahydrofuran (64 ml) and stirred for 1 hour under ice-cooling. To thereaction mixture was added over 15 minutes a solution of the compound(15) (9.11 g, 18.3 mmol) prepared in above (2) in tetrahydrofuran (27ml) and the mixture was continuously stirred for 2 hours at the sametemperature. The reaction mixture was diluted with water (80 ml) andwashed with toluene (2×105 ml). After adjusting the aqueous layer to pH8.1 with 5 N hydrochloric acid (4.8 ml), anhydrous calcium chloride (8.1g, 73 mmol) dissolved in water (16 ml) was added, and the mixture wasextracted with ethyl acetate (2×100 ml). Water (100 ml) was added to theorganic layer, and the aqueous layer was adjusted to below pH 2 with 5 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate and thenthe solvent was distilled off under reduced pressure to provide 11.06 gof the compound (16). The compound (16) was used in the next reactionwithout further purification.

(4) Step 4 Preparation of(5Z)-7-[(1R,2R,3S,5S)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (17) (Compound A))

The compound (16) (11.06 g, 18.3 mmol) prepared in above (3) wasdissolved in dimethyl sulfoxide (22 ml). After adding 4 N sodiumhydroxide (27.5 ml), the mixture was heated at 55° C. for 2 hours withstirring. The reaction mixture was diluted with water (130 ml) andwashed with toluene (2×65 ml). The aqueous layer was acidified with 5 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to provide 8.26 g ofthe crude objective compound which was then dissolved in methanol (40ml) and water (16 ml). The solution was seeded and gradually cooled withstirring. The deposited crystals were filtered and washed with water:methanol (2:5) to provide 6.35 g of the objective compound. Yield:78.6%. The crystals were dissolved in methanol (40 ml). To the solutionwas added water (12 ml) over 7 minutes with stirring. The mixture wasseeded and continuously stirred for 1 hour at 25° C. After adding water(7 ml) over 40 minutes, the mixture was stirred for 1.5 hours at 25° C.The deposited crystals were filtered and washed with water:methanol(3:5) (8 ml) to provide 6.14 g of the objective compound (17) which wasalmost colorless. Yield: 76.0%, mp 145-146° C.

IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469, 1440cm⁻¹

¹H NMR δ(CDCl₃), 300 MHz; 1.02 (1H, d, J=l10.2 Hz), 1.12 and 1.24 (each3H, each s), 1.56-2.55 (14H, m), 4.29 (1H, m), 5.32-5.51 (2H, m), 6.20(1H, d, J=9.3 Hz), 7.01 (1H, dd, J=2.4 and 9.0 Hz), 7.66 (1H, d, J=9.0Hz), 7.69 (1 H,s), 8.03 (1H, d, J=2.4 Hz)

[α]_(D) ²⁴+50.7° (c=1.01, CH₃OH)

Elemental Analyses for C₂₅ H₃₁NO₄S Calculated (%): C, 68.00; H, 7.08; N,3.17; S, 7.26. Found (%): C, 67.84; H, 7.08; N, 3.24; S, 7.31

What is claimed is:
 1. A process for producing a compound of the formula(VI):

wherein R is hydrogen or a hydrogen-protecting group and X is hydrogenor alkyl, and the double bond represents either an E- orZ-configuration, or a pharmaceutically acceptable salt or hydratethereof, which comprises: propargylating a 4-mercaptophenol, andprotecting the hydroxyl group of the 4-mercaptophenol, to yield acompound of the formula (II):

wherein R¹ is a hydroxy-protecting group; oxidizing said compound (II)to yield a compound of the formula (III):

subjecting said compound (III) to a thermal rearrangement reaction toyield a compound of the formula (IV):

wherein R¹ is as defined above; subjecting said compound (IV) tostepwise oxidation of the hydroxymethyl group and optionallydeprotecting said hydroxyl group to yield a compound of the formula (I):

wherein R is as defined above, or a reactive derivative thereof; andsubjecting the compound of the formula (I) or a reactive derivativethereof to the following reactions: (1) reaction with a compound of theformula (V)

wherein X is hydrogen or alkyl; or (2) reaction with a compound of theformula (V′):

or a salt thereof, followed by oxidation and reaction with an ylideunder conditions for a Wittig reaction; and (3) optionally deprotectingsaid hydroxyl group.
 2. A process for producing a compound of theformula (VI):

wherein R is hydrogen or hydroxy-protecting group and X is hydrogen oralkyl, and the double bond represents an E- or Z-configuration, or apharmaceutically acceptable salt or hydrate thereof, which comprisesprotecting the hydroxyl group of 5-hydroxybenzo[b]thiophene to yield acompound of the formula (VII):

wherein R² is a hydroxy-protecting group; reacting said compound (VII)with an acetyl halide under conditions for a Friedel-Crafts reaction toprovide an acetyl group to yield a compound of the formula (VIII):

oxidizing said acetyl group of the compound of the formula (VIII) andoptionally deprotecting said hydroxyl group to yield a compound of theformula (I):

wherein R is as defined above or a reactive derivative thereof; andsubjecting said compound (I) or a reactive derivative thereof to thefollowing reactions: (1) reaction with a compound of the formula (V):

wherein X is as defined above; or (2) reaction with a compound of theformula (V′):

or salt thereof, followed by oxidation and reaction with an ylide underconditions for a Wittig reaction; and (3) optionally deprotecting saidhydroxyl group.
 3. The process for producing a compound of the formula(VI) according to claim 1, wherein said reactive derivative is an acidhalide, acid anhydride, activated ester or acylating agent of saidcompound (VI).
 4. The process for producing a compound of the formula(VI) according to claim 2, wherein said reactive derivative is an acidhalide, acid anhydride, activated ester or acylating agent of saidcompound (VI).